The present invention relates to the use of specifically attenuated live BVD (Bovine Viral Diarrhea) viruses for the preparation of a vaccine for use in the prevention and/or treatment of BVDV infections in breeding stocks of cattle, pregnant cows and for fetal protection in pregnant cows.
The invention also relates to a method of treatment and/or prevention of BVDV infections in the above named group of cattle.
Bovine Viral Diarrhea Virus (BVDV) is the causative agent of BVD and mucosal disease in cattle (Baker, 1987; Moennig and Plagemann, 1992; Thiel et al., 1996). Fetal infection during pregnancy can result in the resorption of the fetus, abortions as well as birth of immunotolerant calves which are persistently infected with BVDV. These calves lack or have very low neutralizing antibody titers and are continuously shedding high amounts of virus. Next to acute or persistently infected bulls these calves are the major source for virus spreading and are therefore of primary importance in the epidemiology of this disease. The major economical impact of BVD results from high abortion rates, stillbirths, fetal resorption, mummification, congenital malformations, and birth of weak and undersized calves. For a detailed review of the pathogenesis, the article of Moennig and Liess of 1995 should be referred to in its entirety.
Two major antigenic groups of BVDV (type I and II) have been described (Becher et al. 1999) which display limited cross neutralizing antibody reactions (Ridpath et al. 1994).
BVDV and other pestiviruses share the ability to cross the placenta of pregnant host animals. Present attenuated live BVDV vaccines also cross the placenta of seronegative heifers and result in clinical symptoms of wild type BVDV infections (see Moennig and Liess, Orban et al. 1983; Liess et al. 1984).
Present vaccines for the prevention and treatment of BVDV infections still have drawbacks (Oirschot et al. 1999).
Killed vaccines (inactivated whole virus) or subunit vaccines (conventionally purified or heterologously expressed purified viral proteins) are most often inferior to live vaccines in their efficacy to produce a full protective immune response even in the presence of adjuvants.
Live BVDV vaccines, although attenuated, are most often associated with serious safety problems. As mentioned above, they cross the placenta of pregnant cows and lead to clinical manifestations in the fetus and/or the induction of persistently infected calves. Therefore, they cannot be applied to breeding herds that comprise pregnant cows. Pregnant cows must to be kept isolated from vaccinated cattle to protect fetuses and may not be vaccinated themselves. Furthermore, revertants of attenuated live BVDV pose a serious threat to cattle. For conventionally derived attenuated viruses wherein the attenuation is attained by conventional multiple passaging, the molecular origin as well as the genetic stability remains unknown and the outbreak of revertants is unpredictable.
Live vaccines with defined mutations as a basis for attenuation would allow to avoid the disadvantages of the present generation of attenuated vaccines. A further advantage of said attenuating mutations lies in their molecular uniqueness which allows for use as distinctive labels for an attenuated pestiviruses and to distinguish them from pestiviruses from the field.
Such live and specifically attenuated pestiviruses with a high potential for induction of immunity as well as a defined basis of attenuation which can also be distinguished from pathogenic pestiviruses are described in the PCT-application PCT/EP 99/03642. In this application it has been demonstrated that pestiviruses can be specifically attenuated by the inactivation of the RNase activity residing in glycoprotein ERNS. The inventors disclose that this attenuation principle is universal to all pestiviruses and particularly suitable for BVDV.
This application discloses an attenuated live vaccine that is superior in its efficacy of induction of immunity to subunit and killed vaccines as well as superior to conventionally attenuated vaccines which are molecularly undefined, unmarked and unpredictable With respect to mutants. From prior art an expert would naturally associate the risk of fetal BVDV infection when vaccinating pregnant cows or cattle in the near vicinity of pregnant cows with an attenuated live virus. This remains a serious drawback limiting the use of such a vaccine.
Therefore, the technical problem underlying this invention was to provide safely attenuated and live BVDV vaccines that can be used for the preparation of a live vaccine for use in the prevention and/or treatment of BVDV infections of pregnant cows or cattle in the presence of pregnant cows.